Klaus Okkenhaug

Research Summary

Our group focuses on how a group of enzymes called phosphoinositide 3-kinases (PI3Ks) are used by cells of the immune system to instruct and coordinate defences against pathogens. Cells of the immune system can express up to eight different forms of PI3K, which act as second messenger signalling molecules within cells that control diverse of cellular functions and genetic programmes.

Our group tries to dissect the unique roles played by individual forms of PI3K with particular focus on their roles in B cells and T cells. We also ask what the effect of inhibiting or enhancing the activity of individual forms of PI3K has on immunity to infections.

Most of our work to date has focused on PI3Kδ. The activation of PI3Kδ is one of the first events that happen inside a T cell or B cell when it first is exposed to a foreign antigen. Because PI3Kδ is expressed at very low levels in other organs in the body, it is thought that targeting PI3K with drugs may be an effective way to suppress immune responses without some of the side effects associated with many immunosuppressive drugs in current use.

We therefore work closely with colleagues in pharmaceutical companies who have developed specific inhibitors against PI3Kδ or other forms of PI3K to help predict and understand the effect of such drugs on the immune system.

DNA methylation changes at a discrete set of sites in the human genome are predictive of chronological and biological age. However, it is not known whether these changes are causative or a consequence of an underlying ageing process. It has also not been shown whether this epigenetic clock is unique to humans or conserved in the more experimentally tractable mouse.

Low-grade systemic inflammation associated to obesity leads to cardiovascular complications, caused partly by infiltration of adipose and vascular tissue by effector T cells. The signals leading to T cell differentiation and tissue infiltration during obesity are poorly understood. We tested whether saturated fatty acid-induced metabolic stress affects differentiation and trafficking patterns of CD4(+) T cells. Memory CD4(+) T cells primed in high-fat diet-fed donors preferentially migrated to non-lymphoid, inflammatory sites, independent of the metabolic status of the hosts. This was due to biased CD4(+) T cell differentiation into CD44(hi)-CCR7(lo)-CD62L(lo)-CXCR3(+)-LFA1(+) effector memory-like T cells upon priming in high-fat diet-fed animals. Similar phenotype was observed in obese subjects in a cohort of free-living people. This developmental bias was independent of any crosstalk between CD4(+) T cells and dendritic cells and was mediated via direct exposure of CD4(+) T cells to palmitate, leading to increased activation of a PI3K p110δ-Akt-dependent pathway upon priming.

The PI3K pathway is hyperactivated in most cancers, yet the capacity of PI3K inhibitors to induce tumor cell death is limited. The efficacy of PI3K inhibition can also derive from interference with the cancer cells' ability to respond to stromal signals, as illustrated by the approved PI3Kδ inhibitor idelalisib in B-cell malignancies. Inhibition of the leukocyte-enriched PI3Kδ or PI3Kγ may unleash antitumor T-cell responses by inhibiting regulatory T cells and immune-suppressive myeloid cells. Moreover, tumor angiogenesis may be targeted by PI3K inhibitors to enhance cancer therapy. Future work should therefore also explore the effects of PI3K inhibitors on the tumor stroma, in addition to their cancer cell-intrinsic impact.